direct oral anticoagulant (DAO)

Description Results NMA

ISTH major or clinically relevant nonmajor bleeding 2.45 [1.32; 4.55]

Cardiovascular death, MI, or stroke 0.61 [0.35; 1.06]

Cardiovascular death, MI, or stroke 0.73 [0.45; 1.18]

ISTH major or clinically relevant nonmajor bleeding 1.78 [0.93; 3.41]

TIMI major or minor bleeding not related to CABG 2.74 [1.79; 4.17]

major bleeding 2.53 [1.47; 4.36]

ISTH major or clinically relevant nonmajor bleeding 2.58 [1.83; 3.62]

any bleeding 2.21 [1.94; 2.51]

major or minor bleeding 2.74 [1.79; 4.17]

net clinical benefit 0.98 [0.84; 1.15]

death 1.08 [0.86; 1.35]

cardiovascular death 0.96 [0.74; 1.25]

fatal bleeding ∞ [NaN; ∞]

ischemic stroke 0.67 [0.40; 1.14]

MI 0.93 [0.77; 1.14]

Cardiovascular death, MI, or stroke 0.99 [0.86; 1.15]

death, MI, stroke, recurrent ischaemia 0.95 [0.82; 1.09]

Thrombotic complication during PCI 0.73 [0.47; 1.12]

apixaban 10 mg once daily (n=318)

vs.

placebo (n=611)

4 arms: 20mg daily, 10mg twice daily, 10mg daily and 2.5mg twice daily. 10mg twice daily and 20mg once daily were discontinued due to an excess of major and minor bleeding

double blind

Parallel groups

Sample size: 318/611

Primary endpoint: major or clinically relevant nonmajor bleeding

FU duration: 6 months

dose-finding study

Apixaban 2.5mg twice daily (n=-9)

vs.

placebo (n=611)

4 arms: 20mg daily, 10mg twice daily, 10mg daily and 2.5mg twice daily. 10mg twice daily and 20mg once daily were discontinued due to an excess of major and minor bleeding

double blind

Sample size: -9/611

Primary endpoint: major or clinically relevant nonmajor bleeding

FU duration: 6 months

dose-finding study

apixaban 5mg twice daily (n=3705)

vs.

placebo (n=3687)

double blind

Parallel groups

Sample size: 3705/3687

Primary endpoint: Cv death, MI, ischemic stroke

FU duration: 8 months

dabigatran 4 dosages (50mg twice daily, 75mg twice daily, 110mg twice daily, 150mg twice daily) (n=1501)

vs.

placebo (n=373)

5 arms: dabigatran 50 mg twice daily (n=372), 75 mg twice daily (n=371), 110 mg twice daily (n=411), 150 mg twice daily (n=351), or placebo (n=373)

double blind

Parallel groups

Sample size: 1501/373

Primary endpoint: Major and minor bleeding

FU duration: 6 months

death, MI, recurrent ischaemia, use of Gp2b3a inhibitor 0.58 [0.34; 0.99]

death, MI 0.56 [0.30; 1.04]

TIMI major or minor bleeding not related to CABG 1.26 [0.63; 2.52]

Thrombotic complication during PCI 1.44 [0.59; 3.52]

otamixaban 5 doses (0·08 mg/kg bolus followed by 0.035, 0.070, 0.105, 0.140, 0.175 mg/kg/h) (n=2792)

vs.

Heparin+eptifibatide (n=449)

6 arms phase 2: otamixaban 5 doses (0·08 mg/kg bolus followed by 0.035, 0.070, 0.105, 0.140, 0.175 mg/kg/h) and unfractionated heparin + eptifi batide

double blind

Parallel groups

Sample size: 2792/449

Primary endpoint: death, MI, recurrent ischaemia, use of Gp2b3a

FU duration: 7 days

dose finding study

death 0.67 [0.53; 0.86]

cardiovascular death 0.66 [0.51; 0.85]

Cardiovascular death, MI, or stroke 0.83 [0.72; 0.96]

major bleeding 3.43 [2.06; 5.71]

ISTH major or clinically relevant nonmajor bleeding 1.75 [1.52; 2.01]

any bleeding 1.75 [1.52; 2.01]

major or minor bleeding 1.75 [1.52; 2.01]

fatal bleeding 0.67 [0.24; 1.88]

MI 0.90 [0.74; 1.08]

death 0.42 [0.33; 0.53]

cardiovascular death 0.42 [0.33; 0.53]

MI 0.53 [0.45; 0.63]

Cardiovascular death, MI, or stroke 0.50 [0.44; 0.57]

major bleeding 4.33 [2.63; 7.12]

ISTH major or clinically relevant nonmajor bleeding 2.27 [1.98; 2.59]

any bleeding 2.27 [1.98; 2.59]

fatal bleeding 1.67 [0.73; 3.82]

major bleeding 17.64 [2.34; 132.76]

ISTH major or clinically relevant nonmajor bleeding 3.36 [2.21; 5.10]

Cardiovascular death, MI, or stroke 0.63 [0.39; 1.01]

major bleeding 3.76 [0.24; 59.88]

Cardiovascular death, MI, or stroke 0.52 [0.23; 1.19]

death, MI, stroke, recurrent ischaemia 0.60 [0.29; 1.25]

ISTH major or clinically relevant nonmajor bleeding 1.71 [0.76; 3.85]

rivaroxaban 2.5 mg twice daily in addition to standard care (n=5174)

vs.

placebo (n=5176)

3 arms: rivaroxaban (2.5 mg twice daily or 5 mg twice daily) in addition to standard care and placebo

double blind

Parallel groups

Sample size: 5174/5176

Primary endpoint: CV death, MI, stroke

FU duration: 13 months

rivaroxaban 5 mg twice daily in addition to standard care (n=5176)

vs.

placebo (n=5176)

3 arms: rivaroxaban (2.5 mg twice daily or 5 mg twice daily) in addition to standard care and placebo

double blind

Sample size: 5176/5176

Primary endpoint: CV death, MI, stroke

FU duration: 13 months

rivaroxaban 5 mg twice daily (n=519)

vs.

placebo (n=1160)

dose finding study: rivaroxaban 5 mg, 10 mg, or 20 mg once daily, 2.5 mg, 5 mg, or 10 mg twice daily and placebo

double blind

Parallel groups

Sample size: 519/1160

Primary endpoint: clinically significant bleeding

FU duration: 6 months

dose-finding study

rivaroxaban 2.5 mg twice daily (n=152)

vs.

placebo (n=1160)

dose finding study: rivaroxaban 5 mg, 10 mg, or 20 mg once daily, 2.5 mg, 5 mg, or 10 mg twice daily and placebo

double blind

Sample size: 152/1160

Primary endpoint: clinically significant bleeding

FU duration: 6 months

dose-finding study

oral ximelagatran at doses of 24 mg, 36 mg, 48 mg, or 60 mg twice daily (n=1245)

vs.

placebo (n=638)

double-blind

Parallel groups

Sample size: 1245/638

Primary endpoint: death, MI, severe recurrent ischaemia

FU duration: 6 months

dose ranging

all death 0.89 [0.81; 0.98] Demonstrated

major bleeding 0.70 [0.61; 0.81] Demonstrated

thrombo-embolic event (cerebral or systemic) 0.80 [0.67; 0.95] Demonstrated

thrombo-embolic event (central or systemic)and fatal or intracranial hemorrhage 0.78 [0.70; 0.87]

haemorragic stroke(or intracerebral hemorrhage) 0.51 [0.35; 0.75]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.79 [0.66; 0.95]

major and clinically relevant non-major bleeding 0.70 [0.63; 0.77]

coronary events 0.88 [0.66; 1.17]

ischemic stroke 0.92 [0.75; 1.14]

Gastrointestinal major bleeding 0.88 [0.68; 1.14]

systemic thrombo-embolic complication 0.88 [0.44; 1.76]

apixaban 5mg twice daily (n=9120)

vs.

warfarin adjusted for an INR between 2 and 3 (n=9081)

double blind

Parallel groups

Sample size: 9120/9081

Primary endpoint: stroke or systemic embolism

FU duration: 1.8 yrs (median)

apixaban 5 or 2.5 mg twice daily (n=222)

vs.

warfarin (n=0)

double blind

Parallel groups

Sample size: 222/0

Primary endpoint: major or clinically relevant non-major bleeding

FU duration: 12 weeks

phase 2

haemorragic stroke(or intracerebral hemorrhage) 0.26 [0.14; 0.49]

fatal stroke(ischemic+hemorrhagic) 0.67 [0.51; 0.89]

non fatal stroke 0.63 [0.43; 0.92]

fatal bleeding 0.82 [0.67; 1.00]

thrombo-embolic event (cerebral or systemic) 0.66 [0.53; 0.82]

ischemic stroke 0.76 [0.59; 0.97]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.64 [0.51; 0.81]

Life threatening major bleeding 0.82 [0.67; 1.00]

Gastrointestinal major bleeding 1.50 [1.20; 1.89]

all death 0.88 [0.77; 1.00]

coronary events 1.29 [0.99; 1.69]

vascular death 0.85 [0.72; 1.00]

major bleeding 0.93 [0.81; 1.07]

Non–life threatening Major bleeding 1.08 [0.90; 1.30]

systemic thrombo-embolic complication 0.85 [0.39; 1.84]

major bleeding 0.80 [0.69; 0.93]

haemorragic stroke(or intracerebral hemorrhage) 0.31 [0.17; 0.56]

Life threatening major bleeding 0.68 [0.56; 0.84]

all death 0.91 [0.80; 1.03]

vascular death 0.90 [0.77; 1.06]

fatal stroke(ischemic+hemorrhagic) 0.95 [0.74; 1.23]

non fatal stroke 0.87 [0.62; 1.23]

thrombo-embolic event (cerebral or systemic) 0.91 [0.74; 1.11]

ischemic stroke 1.11 [0.89; 1.39]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 0.92 [0.75; 1.12]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.92 [0.74; 1.14]

Gastrointestinal major bleeding 1.11 [0.87; 1.42]

Non–life threatening Major bleeding 0.95 [0.79; 1.15]

systemic thrombo-embolic complication 0.79 [0.36; 1.73]

dabigatran 150 mg twice daily (alone or combined with 81- or 325-mg aspirin) (n=166)

vs.

warfarin administered to achieve an international normalized ratio of 2 to 3 for (n=70)

factorial design: Three doses of dabigatran etexilate (50, 150, and 300 mg twice daily) were combined in a 3 3 factorial fashion with no aspirin or 81- or 325-mg aspirin once daily.

double blind

Factorial plan

Sample size: 166/70

Primary endpoint: bleedings

FU duration: 12 weeks

dabigatran 150 mg twice a day (n=6076)

vs.

warfarin adjusted-dose to a 2.0 to 3.0 INR (n=6022)

3 arms: dabigatran 110 mg, 150mg and warfarin

open (blind assessment)

Parallel groups

Sample size: 6076/6022

Primary endpoint: stroke or systemic embolism

FU duration: 2 y (median)

dabigatran 110 mg twice a day (n=6015)

vs.

warfarin adjusted dose to a 2-3 INR (n=6022)

3 arms: dabigatran 110 mg, 150mg and warfarin

open (blind assessment)

Parallel groups

Sample size: 6015/6022

Primary endpoint: stroke or systemic embolism

FU duration: 2 y (median)

Dabigatran 110, 220, 300 mg twice daily (n=-9)

vs.

warfarin (n=-9)

open

Parallel groups

Sample size: -9/-9

Primary endpoint: major bleeding event, ,

FU duration:

vascular death 0.86 [0.77; 0.97]

major bleeding 0.80 [0.71; 0.91]

haemorragic stroke(or intracerebral hemorrhage) 0.47 [0.35; 0.64]

fatal bleeding 0.55 [0.36; 0.84]

Life threatening major bleeding 0.51 [0.38; 0.69]

major and clinically relevant non-major bleeding 0.86 [0.80; 0.92]

Gastrointestinal major bleeding 1.23 [1.01; 1.49]

all death 0.92 [0.83; 1.01]

fatal stroke(ischemic+hemorrhagic) 0.92 [0.68; 1.25]

thrombo-embolic event (cerebral or systemic) 0.87 [0.73; 1.04]

ischemic stroke 1.00 [0.84; 1.20]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.88 [0.75; 1.03]

systemic thrombo-embolic complication 0.65 [0.34; 1.24]

Four Fixed Dose Regimens of edoxaban (DU-176b) (n=1146)

vs.

warfarin (n=0)

double-blind

Parallel groups

Sample size: 1146/0

Primary endpoint: clinically relevant bleeding, •Laboratory marked abnormalities

FU duration: 3 months

phase 2

edoxaban 60mg once daily (n=7035)

vs.

warfarin (INR 2-3) (n=7036)

a third arm received a low dose of edoxaban, 30mg. The allocated dose was halved if any of the following characteristics were present at the time of randomization or during the study: estimated creatinine clearance of 30 to 50 ml per minute, a body weight of 60 kg or less, or the concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors)

double blind

Parallel groups

Sample size: 7035/7036

Primary endpoint: stroke, systemic embolic events and all-cause mortality

FU duration: 2.8 years

edoxaban (DU-176b) (n=-9)

vs.

warfarin (n=-9)

double-blind

Parallel groups

Sample size: -9/-9

Primary endpoint: all bleeding

FU duration:

major bleeding 2.67 [1.74; 4.08]

fatal bleeding 7.14 [1.61; 31.58]

all death 1.12 [0.79; 1.58]

fatal stroke(ischemic+hemorrhagic) 0.00 [0.00; NaN]

thrombo-embolic event (cerebral or systemic) 0.73 [0.40; 1.32]

ischemic stroke 0.71 [0.36; 1.43]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 0.73 [0.40; 1.32]

systemic thrombo-embolic complication 0.00 [0.00; NaN]

subcutaneous idraparinux 2·5 mg weekly (n=2283)

vs.

adjusted-dose vitamin K antagonists (target of an international normalised ratio of 2–3) (n=2293)

open

Parallel groups

Sample size: 2283/2293

Primary endpoint: all stroke and systemic embolism

FU duration: 10.7 months

haemorragic stroke(or intracerebral hemorrhage) 0.58 [0.38; 0.89]

fatal bleeding 0.50 [0.31; 0.80]

Life threatening major bleeding 0.69 [0.53; 0.89]

Gastrointestinal major bleeding 1.46 [1.19; 1.78]

vascular death,TIA,nonfatal stroke or systemic embolism 0.94 [0.84; 1.05]

all death 0.92 [0.82; 1.03]

coronary events 0.80 [0.62; 1.04]

vascular death 0.94 [0.81; 1.09]

major bleeding 1.04 [0.90; 1.20]

fatal stroke(ischemic+hemorrhagic) 0.70 [0.49; 1.02]

thrombo-embolic event (cerebral or systemic) 0.88 [0.75; 1.04]

ischemic stroke 0.99 [0.82; 1.20]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.84 [0.69; 1.01]

major and clinically relevant non-major bleeding 1.03 [0.96; 1.11]

systemic thrombo-embolic complication 0.74 [0.42; 1.31]

Rivaroxaban 20mg p.o. once daily (n=7131)

vs.

Warfarin p.o. once daily titrated to a target INR of 2.5 (range 2.0 to 3.0, inclusive) (n=7133)

double blind

Parallel groups

Sample size: 7131/7133

Primary endpoint: stroke or non-CNS systemic embolism

FU duration: median 1.94 y

non fatal TE events,bleedings and vascular death* 0.71 [0.48; 1.07]

all death 0.99 [0.73; 1.34]

coronary events 1.85 [0.94; 3.61]

vascular death 1.21 [0.77; 1.91]

major bleeding 0.71 [0.44; 1.13]

haemorragic stroke(or intracerebral hemorrhage) 0.44 [0.14; 1.44]

fatal stroke(ischemic+hemorrhagic) 1.11 [0.45; 2.73]

thrombo-embolic event (cerebral or systemic) 0.71 [0.48; 1.07]

ischemic stroke 0.70 [0.45; 1.09]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 0.70 [0.45; 1.09]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.67 [0.44; 1.01]

systemic thrombo-embolic complication 2.00 [0.37; 10.90]

hypertransaminasemia 7.81 [4.58; 13.32]

non fatal TE events,bleedings and vascular death* 1.38 [0.91; 2.10]

all death 0.94 [0.74; 1.21]

coronary events 0.70 [0.43; 1.16]

major bleeding 0.75 [0.54; 1.03]

haemorragic stroke(or intracerebral hemorrhage) 1.00 [0.14; 7.10]

fatal stroke(ischemic+hemorrhagic) 3.34 [0.92; 12.11]

thrombo-embolic event (cerebral or systemic) 1.38 [0.91; 2.10]

ischemic stroke 1.25 [0.81; 1.93]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 1.25 [0.81; 1.93]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 1.24 [0.81; 1.89]

systemic thrombo-embolic complication 6.01 [0.72; 49.84]

ximelegatran 20,40,60 mg twice daily (n=187)

vs.

warfarin standard dose(target INR 2-3) (n=67)

-treatment with either NSAI agents or fibrinolytic agents within the week before the start was prohibited -patient previously receiving warfarin were given ximelegatran once INR value was 1.5 or under/after the end of the study patients who stopped ximelegatran began warfarin 12 to 24 h after last intake.

-SPORTIF II is a dose guiding study -66 patient received 20mg,62 received 40mg,59 received 60 mg

Open

Parallel groups

Sample size: 187/67

Primary endpoint: Thrombo-embolic events and bleedings

FU duration: 16 weeks

it is a dose guiding study

ximelagatran 36 mg twice daily (n=1704)

vs.

warfarin standard dose (target INR 2-3) (n=1703)

Aspirin was used concurrently for at least half the period on study drug by 13% patients assigned to ximelagatran and 10% on warfarin(p=0.01).

Open

Parallel groups

Sample size: 1704/1703

Primary endpoint: All stroke or systemic embolism

FU duration: 17.4 months

Premature termination of study treatment was the result of study endpoint (4% warfarin group,3% ximelegatran) and adverse effects(4% warfarin group,8% ximelegatran group:this difference is related to elevation of liver enzymes in some patients treated with ximelegatran). The trial was a non inferiority trial but the primary analysis was only by intention to treat.

ximelegatran 36 mg twice daily (n=1960)

vs.

warfarin standard dose(target INR 2-3) (n=1962)

Double blind

Parallel groups

Sample size: 1960/1962

Primary endpoint: All stroke and systemic embolism

FU duration: 20 months

major bleeding 17.00 [6.50; 44.44]

CV events 76.00 [66.58; 86.75]

all causes deaths 82.00 [70.52; 95.35]

CV death (IHD+stroke) 78.00 [63.69; 95.53]

fatal stroke 78.00 [63.69; 95.53]

ischemic stroke 51.00 [38.12; 68.22]

all stroke 58.00 [44.13; 76.23]

Rivaroxaban 2.5 mg twice daily alone (n=27400)

vs.

aspirin 100 mg once daily (n=0)

3 arms rivaroxaban and aspirin, rivaroxaban alone, aspirin alone

Sample size: 27400/0

Primary endpoint:

FU duration:

rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily) (n=9152)

vs.

aspirin 100 mg once daily (n=9126)

3 arms rivaroxaban and aspirin, rivaroxaban alone, aspirin alone

double-blind

Parallel groups

Sample size: 9152/9126

Primary endpoint: cardiovascular death, stroke, MI

FU duration: 23 months

death 0.98 [0.87; 1.10]

rivaroxaban at a dose of 2.5 mg twice daily (n=2507)

vs.

placebo (n=2515)

Sample size: 2507/2515

Primary endpoint: death all cause, MI, stroke

FU duration: 21.1 months

DVT (asymptomatic or symptomatic) 0.32 [0.20; 0.51]

proximal DVT 0.35 [0.15; 0.82]

asymptomatic DVT 0.33 [0.20; 0.54]

total VTE and all-cause mortality 0.36 [0.23; 0.56]

major VTE (fatal and non fatal DVT,PE) 0.40 [0.17; 0.94]

death 2.99 [0.31; 28.73]

coronary events 1.66 [0.40; 6.93]

major bleeding 1.22 [0.65; 2.26]

myocardial infarction 2.24 [0.69; 7.27]

non-fatal PE 0.40 [0.08; 2.05]

Symptomatic venous thromboembolism 0.40 [0.04; 4.00]

symptomatic DVT 0.20 [0.02; 1.71]

major or clinically relevant non-major bleeding 0.96 [0.76; 1.21]

apixaban 2.5mg twice daily for 35 days (n=2708)

vs.

enoxaparin 40mg once daily for 35 days (n=2699)

double blind

Parallel groups

Sample size: 2708/2699

Primary endpoint: asymptomatic and symptomatic DVT, PE,all-cause death

FU duration: 35 days (+60)

death ∞ [NaN; ∞]

major bleeding NaN [NaN; NaN]

proximal DVT 0.33 [0.03; 3.10]

asymptomatic DVT 0.63 [0.29; 1.40]

total VTE and all-cause mortality 0.39 [0.08; 1.98]

major VTE (fatal and non fatal DVT,PE) 0.58 [0.28; 1.20]

symptomatic DVT 0.98 [0.06; 15.50]

all bleeding 0.73 [0.26; 2.04]

major or clinically relevant non-major bleeding 0.67 [0.47; 0.97]

death 1.00 [0.20; 4.94]

coronary events 0.50 [0.05; 5.48]

major bleeding 0.50 [0.24; 1.02]

myocardial infarction 0.40 [0.08; 2.05]

DVT (asymptomatic or symptomatic) 0.95 [0.72; 1.26]

proximal DVT 0.79 [0.33; 1.89]

total VTE and all-cause mortality 1.02 [0.78; 1.32]

Symptomatic venous thromboembolism 1.46 [0.72; 2.94]

DVT (asymptomatic or symptomatic) 0.60 [0.50; 0.72]

proximal DVT 0.35 [0.16; 0.74]

total VTE and all-cause mortality 0.62 [0.51; 0.74]

major VTE (fatal and non fatal DVT,PE) 0.50 [0.26; 0.97]

death ∞ [NaN; ∞]

coronary events 1.00 [0.06; 16.05]

major bleeding 0.65 [0.28; 1.49]

myocardial infarction 1.00 [0.06; 15.98]

Symptomatic venous thromboembolism 1.00 [0.35; 2.85]

symptomatic DVT 0.43 [0.11; 1.66]

major or clinically relevant non-major bleeding 0.74 [0.52; 1.05]

apixaban 2.5mg BID for 12 days (n=153)

vs.

enoxaparin 30mg twice daily for 12 days (n=152)

8 arms: apixaban 2.5mg BID, 5mg BID, 10mg BID, 5mgQD, 20mg QD for 12 days, enoxaparin 30mg twice daily, warfarin INR 1.8-3.0

double blind

Parallel groups

Sample size: 153/152

Primary endpoint: VTE events and all-cause death

FU duration: 12 days

phase 2 dose ranging study

apixaban 2.5 mg orally twice daily for 10 to 14 days (n=1599)

vs.

enoxaparin 30mg subcutaneously every 12 hours for 10-14 days (n=1596)

double blind

Parallel groups

Sample size: 1599/1596

Primary endpoint: a- and symptomatic DVT, non fatal PE, death

FU duration: 10-14 days

apixaban 2.5mg twice daily during 12 days (n=1528)

vs.

enoxaparin 40mg once daily 12 days (n=1529)

"European" enoxaprin regimen

double blind

Parallel groups

Sample size: 1528/1529

Primary endpoint: asymptomatic and symptomatic proximal DVT, PE, VTE-related death

FU duration: 12 days

Symptomatic deep vein thrombosis during follow-up 0.31 [0.12; 0.86]

Major bleeding during follow-up 2.53 [0.98; 6.50]

Asymptomatic deep vein thrombosis during follow-up. 1.11 [0.76; 1.64]

VTE 0.89 [0.63; 1.24]

fatal PE NaN [NaN; NaN]

PE 0.88 [0.32; 2.42]

Venous thromboembolism or death 0.89 [0.63; 1.24]

proximal deep-vein thrombosis 0.96 [0.66; 1.39]

apixaban, administered orally at a dose of 2.5 mg twice daily for 30 days (n=3255)

vs.

enoxaparin, administered subcutaneously at a dose of 40 mg once daily for 6 to 14 days (n=3273)

double-blind

Sample size: 3255/3273

Primary endpoint:

FU duration: 30 days

Symptomatic pulmonary embolism during follow-up 0.79 [0.63; 0.99]

proximal deep-vein thrombosis 0.79 [0.63; 0.99]

Major bleeding during follow-up 1.19 [0.67; 2.12]

VTE 0.81 [0.65; 1.01]

Symptomatic deep vein thrombosis during follow-up 0.81 [0.65; 1.00]

net clinical benefit 0.83 [0.67; 1.02]

Venous thromboembolism or death 0.81 [0.65; 1.01]

betrixaban (at a dose of 80 mg once daily) for 35 to 42 days (n=3759)

vs.

subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days (n=3754)

double-blind

Parallel groups

Sample size: 3759/3754

Primary endpoint: asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism

FU duration:

death ∞ [NaN; ∞]

major bleeding 1.29 [0.70; 2.37]

proximal DVT 0.57 [0.32; 1.00]

distal DVT 0.94 [0.53; 1.66]

non-fatal PE 1.70 [0.41; 7.09]

asymptomatic DVT 0.73 [0.49; 1.08]

total VTE and all-cause mortality 0.90 [0.63; 1.29]

major VTE (fatal and non fatal DVT,PE) 0.78 [0.48; 1.27]

symptomatic DVT 6.03 [0.73; 49.98]

symptomatic DVT 8.89 [1.13; 70.07]

death NaN [NaN; NaN]

coronary events 0.72 [0.31; 1.68]

major bleeding 0.83 [0.42; 1.63]

proximal DVT 0.90 [0.55; 1.49]

distal DVT 1.50 [0.90; 2.50]

non-fatal PE 0.33 [0.03; 3.16]

asymptomatic DVT 1.15 [0.82; 1.63]

total VTE and all-cause mortality 1.28 [0.93; 1.78]

major VTE (fatal and non fatal DVT,PE) 1.09 [0.70; 1.70]

coronary events 0.99 [0.06; 15.86]

dabigatran etexilate 220 mg q.d. for 28-35 days (n=1157)

vs.

Enoxaparin 40 mg q.d. for 23-35 days (n=1162)

3 arms dabigatran 220mg, 150mg and placebo

double blind

Parallel groups

Sample size: 1157/1162

Primary endpoint: total VTE and all-cause mortality

FU duration: 28-35 days, median 33d

dabigatran etexilate 150 mg q.d. 28-35 days (n=1174)

vs.

Enoxaparin 40 mg q.d. for 28-25 days (n=1162)

3 arms dabigatran 220mg, 150mg and placebo

double blind

Sample size: 1174/1162

Primary endpoint: total VTE and all-cause mortality

FU duration: 28-35 days, median 33d

dabigatran 220mg once daily for 28-35 Days (n=1010)

vs.

enoxaparin 40mg subcutaneous once daily for 28-35 Days (n=1003)

double-blind

Parallel groups

Sample size: 1010/1003

Primary endpoint: venous thromboembolism or death

FU duration: 28-35 days (mean 32d)

total VTE and all-cause mortality 1.23 [1.03; 1.47]

coronary events 1.05 [0.48; 2.31]

major bleeding 0.42 [0.15; 1.19]

proximal DVT 1.49 [0.67; 3.33]

distal DVT 1.20 [0.99; 1.45]

major VTE (fatal and non fatal DVT,PE) 1.51 [0.79; 2.91]

major or clinically relevant non-major bleeding 0.86 [0.52; 1.41]

death 1.01 [0.06; 16.19]

coronary events 1.26 [0.40; 3.99]

major bleeding 1.14 [0.46; 2.78]

proximal DVT 0.82 [0.40; 1.69]

distal DVT 1.02 [0.85; 1.21]

asymptomatic DVT 1.00 [0.85; 1.18]

total VTE and all-cause mortality 0.97 [0.82; 1.13]

major VTE (fatal and non fatal DVT,PE) 0.73 [0.36; 1.47]

symptomatic DVT 0.13 [0.02; 1.01]

major or clinically relevant non-major bleeding 1.11 [0.76; 1.63]

death 0.98 [0.06; 15.70]

major bleeding 0.99 [0.39; 2.47]

proximal DVT 1.03 [0.54; 1.98]

distal DVT 1.07 [0.91; 1.27]

non-fatal PE ∞ [NaN; ∞]

asymptomatic DVT 1.10 [0.94; 1.29]

total VTE and all-cause mortality 1.07 [0.92; 1.25]

major VTE (fatal and non fatal DVT,PE) 1.08 [0.58; 2.01]

symptomatic DVT 0.37 [0.10; 1.37]

major or clinically relevant non-major bleeding 1.22 [0.84; 1.78]

distal DVT 1.33 [1.10; 1.59]

total VTE and all-cause mortality 1.33 [1.12; 1.58]

death ∞ [NaN; ∞]

major bleeding 0.42 [0.15; 1.17]

non-fatal PE 0.00 [0.00; NaN]

major VTE (fatal and non fatal DVT,PE) 1.36 [0.70; 2.63]

major or clinically relevant non-major bleeding 0.82 [0.49; 1.34]

dabigatran etexilate 220 mg for 12-15 days (n=862)

vs.

Enoxaparin 30mg SC BID after surgery for 12-15 days (n=876)

double blind

Parallel groups

Sample size: 862/876

Primary endpoint: total VTE and all-cause mortality

FU duration: 12-15 days, median 14d

dabigatran etexilate 220 mg q.d. 6-10 days (n=694)

vs.

Enoxaparin 40 mg q.d. for 6-10 days (n=699)

double blind

Sample size: 694/699

Primary endpoint: total VTE and all-cause mortality

FU duration: 6-10 days, mean 8 days

dabigatran etexilate 150 mg q.d. for 6-10 days (n=708)

vs.

Enoxaparin 40 mg q.d. for 6-10 days (n=699)

double blind

Parallel groups

Sample size: 708/699

Primary endpoint: total VTE and all-cause mortality

FU duration: 6-10 days, mean 8 days

dabigatran etexilate 150 mg q.d. for 12-15 days (n=877)

vs.

enoxaparin 30 mg SC BID after surgery for 12-15 days (n=876)

double blind

Sample size: 877/876

Primary endpoint: total VTE and all-cause mortality

FU duration: 12-15 days, median 14d

distal DVT 0.36 [0.15; 0.92]

asymptomatic DVT 0.38 [0.16; 0.89]

major VTE (fatal and non fatal DVT,PE) 0.34 [0.14; 0.86]

proximal DVT 0.49 [0.04; 5.33]

symptomatic DVT NaN [NaN; NaN]

edoxaban 30 mg once daily for 11 to 14 days (n=255)

vs.

subcutaneous enoxaparin 2,000 IU, equivalent to 20 mg, twice daily (BID) for 11 to 14 days (n=248)

double-blind

Parallel groups

Sample size: 255/248

Primary endpoint: all DVT,PE

FU duration:

DVT (asymptomatic or symptomatic) 0.42 [0.22; 0.79]

distal DVT 0.36 [0.17; 0.73]

total VTE and all-cause mortality 0.42 [0.22; 0.79]

proximal DVT 0.95 [0.20; 4.59]

non-fatal PE NaN [NaN; NaN]

DVT (asymptomatic or symptomatic) 0.23 [0.12; 0.43]

proximal DVT 0.03 [0.00; 0.23]

total VTE and all-cause mortality 0.30 [0.18; 0.51]

major VTE (fatal and non fatal DVT,PE) 0.12 [0.04; 0.34]

death 0.98 [0.24; 3.90]

coronary events 0.49 [0.12; 1.95]

major bleeding 3.02 [0.61; 14.95]

distal DVT 0.49 [0.24; 1.00]

non-fatal PE 3.91 [0.44; 34.92]

Symptomatic venous thromboembolism 0.55 [0.20; 1.48]

DVT (asymptomatic or symptomatic) 0.20 [0.11; 0.35]

proximal DVT 0.11 [0.05; 0.29]

distal DVT 0.34 [0.16; 0.71]

total VTE and all-cause mortality 0.21 [0.13; 0.35]

Symptomatic venous thromboembolism 0.20 [0.06; 0.69]

major VTE (fatal and non fatal DVT,PE) 0.12 [0.05; 0.28]

death 0.34 [0.07; 1.66]

coronary events 1.33 [0.30; 5.95]

major bleeding 1.00 [0.06; 15.98]

non-fatal PE 0.25 [0.03; 2.25]

major or clinically relevant non-major bleeding 1.20 [0.93; 1.54]

rivaroxaban 10mg daily for 5–9 days (n=142)

vs.

once-daily subcutaneous enoxaparin dose of 40 mg for 5–9 days (n=157)

dose finding study (doses of 5, 10, 20, 30, or 40 mg)

double blind

Parallel groups

Sample size: 142/157

Primary endpoint: any DVT, PE, all cause death

FU duration: 5-9 days

rivaroxaban 10mg once daily for 35 days (n=2266)

vs.

enoxaparin 40mg subcutaneous once daily for 31-39 days (n=2275)

double blind

Parallel groups

Sample size: 2266/2275

Primary endpoint: DVT, PE, death

FU duration: 36 days (range 30-42)

extended thromboprophylaxis with rivaroxaban 10mg once daily for 31-39 days (n=1252)

vs.

enoxaparin 40mg subcutaneous once daily for 10-14 days (n=1257)

double blind

Parallel groups

Sample size: 1252/1257

Primary endpoint: DVT, PE , all cause death

FU duration: 30-42 days

major bleeding 0.00 [0.00; NaN]

DVT (asymptomatic or symptomatic) 0.53 [0.41; 0.68]

distal DVT 0.53 [0.41; 0.70]

total VTE and all-cause mortality 0.51 [0.39; 0.65]

Symptomatic venous thromboembolism 0.34 [0.15; 0.75]

major VTE (fatal and non fatal DVT,PE) 0.38 [0.18; 0.82]

death 0.00 [0.00; NaN]

coronary events 0.51 [0.05; 5.59]

major bleeding 1.19 [0.40; 3.53]

myocardial infarction 0.51 [0.05; 5.61]

proximal DVT 0.48 [0.22; 1.05]

non-fatal PE 0.00 [0.00; NaN]

proximal DVT 0.23 [0.07; 0.80]

total VTE and all-cause mortality 0.69 [0.51; 0.92]

death 0.66 [0.11; 3.94]

coronary events 0.33 [0.03; 3.16]

major bleeding 2.47 [0.78; 7.86]

myocardial infarction 0.20 [0.02; 1.69]

distal DVT 0.82 [0.57; 1.17]

non-fatal PE 0.49 [0.15; 1.64]

asymptomatic DVT 0.72 [0.51; 1.01]

Symptomatic venous thromboembolism 0.60 [0.29; 1.27]

major VTE (fatal and non fatal DVT,PE) 0.59 [0.30; 1.16]

symptomatic DVT 0.60 [0.22; 1.63]

major or clinically relevant non-major bleeding 1.34 [0.86; 2.07]

BAY 59-7939 5mg b.i.d. for 5–9 days (n=102)

vs.

enoxaparin 30 mg b.i.d. for 5–9 days (n=105)

dose ranging study with doses 2.5, 5, 10, 20, and 30 mg

double blind

Parallel groups

Sample size: 102/105

Primary endpoint:

FU duration: 5-9 days

rivaroxaban 10 mg once daily for 10- 14 days (n=1254)

vs.

enoxaparin 40 mg subcutaneous once daily for 10-14 days (n=1277)

double blind

Parallel groups

Sample size: 1254/1277

Primary endpoint: DVT, PE all cause mortality

FU duration: 13-17 days

rivaroxaban 10mg once daily for 10 to 14 days (n=1584)

vs.

enoxaparin 30 mg twice daily by subcutaneous injection for 10-14 days (n=1564)

double blind

Parallel groups

Sample size: 1584/1564

Primary endpoint: total VTE events

FU duration: 40 days

Symptomatic deep vein thrombosis during follow-up 0.44 [0.22; 0.88]

Venous thromboembolism or death 0.73 [0.54; 0.98]

Clinically relevant bleeding 1.66 [1.17; 2.35]

All-cause death during follow-up 0.80 [0.58; 1.10]

Major bleeding during follow-up 1.88 [0.84; 4.22]

VTE 0.76 [0.52; 1.10]

once-daily rivaroxaban at a dose of 10 mg (with the dose adjusted for renal insufficiency) , begun at hospital discharge and continued for 45 days (n=6007)

vs.

placebo (n=6012)

double blind

Sample size: 6007/6012

Primary endpoint: symptomatic venous thromboembolism or death due to venous thromboembolism

FU duration:

recurrent VTE 0.33 [0.22; 0.49]

Major bleeding 0.49 [0.09; 2.69]

major or clinically relevant nonmajor bleeding 1.21 [0.70; 2.11]

recurrent VTE 0.36 [0.25; 0.53]

Major bleeding 0.25 [0.03; 2.28]

major or clinically relevant nonmajor bleeding 1.62 [0.96; 2.74]

Extended Treatment with apixaban 2.5 mg twice daily 12 months (n=842)

vs.

placebo (n=829)

3 arms: apixaban 2.5mg, 5mg twice daily, placebo

double blind

Parallel groups

Sample size: 842/829

Primary endpoint:

FU duration: 12 mo

Extended Treatment with apixaban 5 mg twice daily 12 months (n=815)

vs.

placebo (n=829)

3 arms: apixaban 2.5mg, 5mg twice daily, placebo

double blind

Sample size: 815/829

Primary endpoint:

FU duration: 12 mo

Major bleeding 0.31 [0.17; 0.55]

recurrent DVT only 0.61 [0.35; 1.06]

death 0.79 [0.53; 1.19]

All deaths 0.79 [0.53; 1.19]

non fatal PE 1.19 [0.68; 2.06]

fatal PE 0.50 [0.05; 5.57]

Symptomatic nonfatal pulmonary embolism 1.19 [0.68; 2.06]

recurrent VTE during treatment 0.84 [0.60; 1.18]

Symptomatic deep-vein thrombosis 0.61 [0.35; 1.06]

Death related to venous thromboembolism 0.85 [0.38; 1.90]

recurrent VTE 0.84 [0.60; 1.18]

apixaban 5 mg twice-daily, 10 mg twice-daily, or 20 mg once-daily for 84-91 days (n=358)

vs.

low molecular weight heparin followed by vitamin K antagonists (n=118)

open

Parallel groups

Sample size: 358/118

Primary endpoint: recurrent VTE or asymptomatic deterioration in the

FU duration:

dose-ranging study; the primary efficacy endpoint was the composite of symptomatic recurrent venous thromboembolism and asymptomatic deterioration of bilateral compression ultrasound or perfusion lung scan

apixaban 10 mg twice daily for 7 days then 5 mg, twice daily, 6 months (n=2691)

vs.

conventional therapy: enoxaparin 1mg/kg twice daily until INR>=2 then warfarin for an INR between 2-4, once daikly, 6 months (n=2704)

double blind

Parallel groups

Sample size: 2691/2704

Primary endpoint: Venous thromboembolic recurrence or death

FU duration: 6 mo

any bleeding 0.74 [0.65; 0.85]

major or clinically relevant nonmajor bleeding 0.55 [0.42; 0.72]

All deaths 0.89 [0.47; 1.71]

Major bleeding 0.52 [0.27; 1.01]

Symptomatic nonfatal pulmonary embolism 1.99 [0.68; 5.82]

recurrent VTE during treatment 1.44 [0.79; 2.62]

Death related to venous thromboembolism 1.00 [0.06; 15.93]

recurrent VTE 1.44 [0.79; 2.62]

dabigatran 150 mg twice daily for an additional period of 6 to 36 months (n=1430)

vs.

warfarin (to maintain an international normalized ratio of 2.0 to 3.0) for an additional period of 6 to 36 months (n=1426)

dabigatran 150 mg twice daily or with warfarin (to maintain an international normalized ratio of 2.0 to 3.0) for an additional period of 6 to 36 months after 3 to 12 months of anticoagulant therapy

double-blind

Parallel groups

Sample size: 1430/1426

Primary endpoint: recurrent symptomatic VTE and related deaths

FU duration: 6 to 36 months

recurrent VTE during treatment 0.08 [0.02; 0.25]

recurrent VTE 0.08 [0.02; 0.25]

All deaths 0.00 [0.00; NaN]

Major bleeding ∞ [NaN; ∞]

dabigatran 150 mg twice daily for an additional period of 6 months (n=681)

vs.

placebo (n=662)

patients randomized after 6-18 months of anticoagulant therapy

double-blind

Parallel groups

Sample size: 681/662

Primary endpoint: recurrent symptomatic VTE and related deaths

FU duration:

any bleeding 0.73 [0.62; 0.86]

All deaths 0.99 [0.55; 1.81]

Major bleeding 0.83 [0.46; 1.49]

Symptomatic nonfatal pulmonary embolism 1.84 [0.74; 4.61]

recurrent VTE during treatment 1.10 [0.66; 1.84]

Symptomatic deep-vein thrombosis 0.88 [0.45; 1.72]

Death related to venous thromboembolism 0.33 [0.03; 3.18]

recurrent VTE 1.05 [0.66; 1.70]

any bleeding 0.71 [0.60; 0.84]

death 1.01 [0.59; 1.76]

Major bleeding 0.69 [0.36; 1.33]

recurrent VTE during treatment 1.09 [0.65; 1.81]

recurrent VTE 1.09 [0.65; 1.81]

dabigatran 150 mg twice daily in a fixed-dose (n=1274)

vs.

warfarin dose-adjusted to an INR between 2.0 and 3.0 (n=1265)

double blind

Parallel groups

Sample size: 1274/1265

Primary endpoint: recurrent VTE or VTE-related death

FU duration: 6 months

dabigatran, 150 mg twice daily, for 6 months (n=1294)

vs.

warfarin, dose-adjusted to an INR of 2.0 and 3.0, for 6 months (n=1295)

double-blind

Parallel groups

Sample size: 1294/1295

Primary endpoint: symptomatic recurrence + related death

FU duration: 6 months

any bleeding 0.85 [0.79; 0.92]

major or clinically relevant nonmajor bleeding 0.83 [0.72; 0.95]

recurrent DVT only 0.89 [0.71; 1.12]

Major bleeding 0.85 [0.60; 1.21]

non fatal PE 0.83 [0.57; 1.21]

fatal PE 1.34 [0.30; 5.96]

recurrent VTE during treatment 0.83 [0.60; 1.14]

heparin then edoxaban 60mg daily (30mg if creatine clearnce of 30 to 50 ml/min or <60kg) for 3 to 12 months (n=4143)

vs.

heparin then warfarin (n=4149)

double-blind

Parallel groups

Sample size: 4143/4149

Primary endpoint: recurrent symptomatic venous thromboembolism

FU duration:

Major hemorrhage 1.77 [1.03; 3.04]

recurrent venous thromboembolism or major bleeding 0.97 [0.70; 1.35]

All-cause mortality 1.12 [0.92; 1.37]

Recurrent DVT/DVT extension (symptomatic) 0.71 [0.48; 1.06]

recurrent VTE 0.71 [0.48; 1.06]

low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily. Treatment was given for atleast 6 months and up to 12 months. (n=522)

vs.

subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (n=524)

open label

Sample size: 522/524

Primary endpoint: recurrent venous thromboembolism or major bleeding at12 months

FU duration:

all bleeding 0.89 [0.50; 1.59]

deaths at 6 months 0.99 [0.66; 1.48]

Recurrent DVT/DVTextension (total) 0.38 [0.14; 1.06]

once-weekly subcutaneous injection of idraparinux (2.5 mg) for 6 months (n=220)

vs.

standard treatment for three months (8%) or six months (92%) (n=201)

Parallel groups

Sample size: 220/201

Primary endpoint:

FU duration: 6 months

recurrent DVT only 0.16 [0.06; 0.41]

non fatal PE 0.15 [0.03; 0.67]

recurrent VTE 0.19 [0.09; 0.40]

major or clinically relevant nonmajor bleeding 5.07 [2.28; 11.31]

death 0.49 [0.04; 5.43]

All deaths 0.49 [0.04; 5.43]

Major bleeding ∞ [NaN; ∞]

fatal PE 0.00 [0.00; NaN]

Death related to venous thromboembolism 0.99 [0.06; 15.74]

rivaroxaban 20 mg once-daily for an additional 6 or 12 months (n=602)

vs.

placebo (n=595)

double blind

Parallel groups

Sample size: 602/595

Primary endpoint: symptomatic recurrent VTE

FU duration:

recurrent DVT only 0.50 [0.26; 0.94]

All deaths 0.77 [0.51; 1.17]

Major bleeding 0.70 [0.35; 1.38]

non fatal PE 1.10 [0.59; 2.08]

fatal PE ∞ [NaN; ∞]

Symptomatic nonfatal pulmonary embolism 1.10 [0.59; 2.08]

recurrent VTE during treatment 0.70 [0.46; 1.07]

Death related to venous thromboembolism 0.66 [0.19; 2.35]

recurrent VTE 0.70 [0.46; 1.07]

rivaroxaban 20, 30, or 40 mg once daily (n=-9)

vs.

low-molecular-weight heparin followed by vitamin K antagonists (n=-9)

open

Sample size: -9/-9

Primary endpoint:

FU duration:

rivaroxaban 15 mg twice daily for 3 weeks, then 20 mg daily (n=1731)

vs.

enoxaparin 1 mg/kg twice daily >=5 days, then warfarin with target INR between 2-3 (n=1718)

treatment duration (3, 6, or 12 months) decided by physicians. treatment duration of 6 months in 63%, 3 mo in 12% and 12 mo in 25%

open (assessor-blind)

Parallel groups

Sample size: 1731/1718

Primary endpoint: Symptomatic recurrent VTE

FU duration:

rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) for 3, 6, or 12 months (n=2419)

vs.

standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist (n=2413)

open

Parallel groups

Sample size: 2419/2413

Primary endpoint: symptomatic recurrent venous thromboembolism

FU duration: 9.8 months

recurrent VTE 0.43 [0.19; 0.98]

all bleeding 3.76 [1.63; 8.68]

Major hemorrhage 1.83 [0.68; 4.94]

recurrent venous thromboembolism or major bleeding 0.54 [0.33; 0.89]

Major hemorrhage 0.42 [0.18; 0.98]

All-cause mortality 0.93 [0.64; 1.35]

all bleeding 0.80 [0.54; 1.19]

recurrent VTE 0.67 [0.35; 1.29]

rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months) (n=203)

vs.

dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) (n=203)

open-design

Sample size: 203/203

Primary endpoint:

FU duration:

pilot trial

rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily (n=354)

vs.

(enoxaparin1·0 mg/kg twice daily and warfarin or acenocoumarol; international normalised ratio 2·0–3·0 (n=301)

Sample size: 354/301

Primary endpoint:

FU duration:

sub group analysis

death 0.25 [0.08; 0.79]

non fatal PE 0.10 [0.01; 0.73]

recurrent VTE 0.27 [0.11; 0.67]

major or clinically relevant nonmajor bleeding 3.11 [1.48; 6.56]

recurrent DVT only 0.29 [0.08; 1.02]

Major bleeding ∞ [NaN; ∞]

fatal PE 2.09 [0.19; 23.00]

once-weekly injections of 2.5 mg of idraparinux for 6 months (n=594)

vs.

placebo (n=621)

Parallel groups

Sample size: 594/621

Primary endpoint:

FU duration: 6 months

Recurrent DVT/DVT extension (symptomatic) 0.17 [0.09; 0.31]

VTA 0.24 [0.15; 0.40]

All-cause mortality 0.86 [0.29; 2.53]

Major hemorrhage 1.20 [0.37; 3.90]

any bleedings 1.21 [0.96; 1.51]

ximelagatran 24 mg twice daily for 18 months (n=612)

vs.

placebo for 18 months (n=611)

double blind

Parallel groups

Sample size: 612/611

Primary endpoint: symptomatic recurrent venous

FU duration: 18 months

oral ximelagatran (24, 36, 48 or 60 mg twice daily) for 2 weeks (n=-9)

vs.

dalteparin and warfarin for 2 weeks (n=-9)

Sample size: -9/-9

Primary endpoint:

FU duration:

extended treatment with Ximelagatran 24mg twice daily after initial anticoagulant treatment for 6 months (n=-9)

vs.

placebo (initial anticoagulant treatment for 6 months) (n=-9)

single blind and outcome ass.

Parallel groups

Sample size: -9/-9

Primary endpoint:

FU duration: 18 months